Chen Wei, Yi Jin Kyu, Shimane Tetsu, Mehrazarin Shebli, Lin Yi-Ling, Shin Ki-Hyuk, Kim Reuben H, Park No-Hee, Kang Mo K
School of Dentistry, University of California at Los Angeles, Los Angeles, CA 90095, USA.
School of Dentistry, University of California at Los Angeles, Los Angeles, CA 90095, USA, School of Dentistry, Kyung Hee University, Seoul 130-872, Korea.
Carcinogenesis. 2016 May;37(5):500-10. doi: 10.1093/carcin/bgw027. Epub 2016 Mar 1.
Grainyhead-like 2 (GRHL2) is one of the three mammalian homologues of Drosophila Grainyhead involved in epithelial morphogenesis. We recently showed that GRHL2 also controls normal epithelial cell proliferation and differentiation. In this study, we investigated the role of GRHL2 in oral carcinogenesis and the underlying mechanism. GRHL2 expression was elevated in cells and tissues of oral squamous cell carcinomas (OSCCs) compared with normal counterparts. Knockdown of GRHL2 resulted in the loss of in vivo tumorigenicity, cancer stemness and epithelial phenotype of oral cancer cells. GRHL2 loss also inhibited oral cancer cell proliferation and colony formation. GRHL2 regulated the expression of miR-200 family and Octamer-binding transcription factor 4 (Oct-4) genes through direct promoter DNA binding. Overexpression of miR-200 genes in the oral cancer cells depleted of GRHL2 partially restored the epithelial phenotype, proliferative rate and cancer stemness, indicating that miR-200 genes in part mediate the functional effects of GRHL2. Taken together, this study demonstrates a novel connection between GRHL2 and miR-200, and supports protumorigenic effect of GRHL2 on OSCCs.
颗粒头样蛋白2（GRHL2）是果蝇颗粒头蛋白在哺乳动物中的三个同源物之一，参与上皮形态发生。我们最近发现，GRHL2还控制正常上皮细胞的增殖和分化。在本研究中，我们调查了GRHL2在口腔癌发生中的作用及其潜在机制。与正常组织相比，口腔鳞状细胞癌（OSCC）的细胞和组织中GRHL2表达升高。敲低GRHL2导致口腔癌细胞体内致瘤性、癌症干性和上皮表型丧失。GRHL2缺失还抑制口腔癌细胞增殖和集落形成。GRHL2通过直接结合启动子DNA来调控miR-200家族和八聚体结合转录因子4（Oct-4）基因的表达。在GRHL2缺失的口腔癌细胞中过表达miR-200基因可部分恢复上皮表型、增殖率和癌症干性，表明miR-200基因部分介导了GRHL2的功能效应。综上所述，本研究揭示了GRHL2与miR-200之间的新联系，并支持GRHL2对OSCC的促肿瘤作用。
